Understanding the mechanisms of green tea EGCG against amyloid β oligomer neurotoxicity through computational studies.

Oligomeric species of amyloid β peptide (Aβ) are pivotal in Alzheimer's disease (AD) pathogenesis, making them valuable therapeutic targets. Currently, there is no cure or preventive therapy available for AD, with only a few therapeutics offering temporary alleviation of symptoms. Natural products (NPs) are now considered promising anti-amyloid agents. Green tea catechins have garnered considerable attention due to their ability to remodel the toxic amyloid β peptide oligomers (AβOs) into non-toxic assemblies. Nevertheless, the precise molecular mechanism underlying their effects on AβOs remains unclear. In this study, we employ a combination of binding site prediction, molecular docking, and dynamics simulations to gain mechanistic insights into the binding of the potent anti-amyloid epigallocatechin-3-gallate (EGCG) and the less effective catechin, epicatechin (EC), on the structure of pore-forming Aβ tetramers (PDB ID 6RHY). This recently elucidated structure represents AβO (1-42) with two faces of the hydrophobic β-sheet core and hydrophilic edges. Our simulations revealed three potential druggable binding sites within the AβO: two in hydrophilic edges and one in the β-sheet core. Although both catechins bind via hydrogen bond (H-bond) and aromatic interactions to the three potential binding sites, EGCG interacted with key residues more efficiently than EC. We propose that EGCG may remodel AβOs preventing pore formation by binding to the hydrophilic edge binding sites. Additionally, EGCG interacts with key residues in the oligomer's β-sheet core binding site, crucial for fibrillar aggregation. A better understanding of how anti-amyloid compounds remodelling AβOs could be valuable for the development of new therapeutic strategies targeting Aβ in AD. Further experimental validation using point mutations involving key residues could be useful to define whether the establishment of these interactions is crucial for the EGCG remodelling effect.